5‘-Substituted Adenosine Analogs as New High-Affinity Partial Agonists for the Adenosine A1 Receptor

Abstract

5‘-(Alkylthio)-, 5‘-(methylseleno)-, and 5‘-(alkylamino)-substituted analogues of N⁶-cyclopentyladenosine (CPA) were synthesized in 30−50% overall yields. The affinities of these compounds for the adenosine A₁ and A_2A receptors were determined in rat brain membranes. The 5‘-substituted CPA analogues proved selective for the adenosine A₁ receptors, displaying affinities in the nanomolar range. The compounds were also evaluated for their ability to stimulate [³⁵S]GTPγS binding, also in rat brain membranes. The K_i values in receptor binding studies corresponded well to the EC₅₀ values thus obtained. Intrinsic activities of the compounds were tested in vitro by determining the GTP shift in receptor binding studies as well as the maximal binding of [³⁵S]GTPγS. It appeared that the 5‘-thio and 5‘-seleno derivatives in particular behaved as partial agonists.